Indanol compounds

ABSTRACT

A compound of formula (I): ##STR1## wherein R 1 , R 2 , R 3 , R 4 , X-Y, A, Z and Z&#39; are as defined in the description, in the form of the cis or trans isomers each in racemic or optically active form, and acid addition salts thereof, and medicinal products containing the same are useful in the treatment of diseases of the central nervous system or of manifestations of pain.

FIELD OF THE INVENTION

The present invention relates to new indanol compounds. The compounds ofthe present invention find advantageous therapeutic use in the treatmentof diseases of the central nervous system or of manifestations of pain.

DESCRIPTION OF THE PRIOR ART

A large number of serotonin receptor sub-types have been identifiedhitherto. Within the 5-HT₁ receptor class itself, molecular biologystudies and pharmacological studies have enabled sub-division to be madebetween five different receptors, 5-HT_(1A), 5-HT_(1B), 5-HT_(1D),5-HT_(1E), 5-HT_(1F), (Humphrey, P. P. A. et al., A proposed newnomenclature for 5-HT receptors, Trends in Pharmacological Sciences,1993, 14, 233).

Previous studies carried out in the Applicant's laboratories (U.S. Pat.No. 5,194,437) had made it possible to show that compounds of the type:##STR2## had 5-HT_(1A) serotoninergic receptor antagonist properties.

Research carried out since then in the Applicant's laboratories hasenabled the identification of substances that differ structurally fromthe preceding substances by the presence of an alcohol function on thepentagonal ring of the indane group, which makes the new compounds muchsafer to use owing to the better receptor selectivity of the compoundsof the invention. It has in fact been possible to increase the ratiobetween the 5-HT_(1A) and α₁ affinities on the one hand and the5-HT_(1A) and D₂ affinities on the other hand by minimising the effectsat the α₁ and D₂ sites. The new compounds thus behave like much moreselective 5-HT_(1A) ligands and consequently induce fewer side-effects.The prior art can also be illustrated by Patent WO 87/02035 which claimscyclic amino alcohols of general formula: ##STR3## wherein NR₃ R₄ maybe: ##STR4## However, those compounds are used in the treatment ofcardiovascular diseases (antihypertensives, platelet anti-aggregants,spasmolytics, etc.) and could not have inspired the compounds of thepresent invention nor their use in the areas claimed hereinafter.

In vivo studies carried out with the compounds of the present inventionhave confirmed the results obtained in vitro in the binding studies andhave identified the site of action, since the 5HT_(1A) receptors arelocated both at the pre-synaptic and post-synaptic levels.

Indeed, recording of the unitary extracellular electrical activity inthe dorsal nucleus of the raphe in rats makes it possible to determinethe 5-HT_(1A) agonist or antagonist character at the pre-synaptic level,whilst the body temperature test in rats makes it possible todemonstrate the post-synaptic agonist or antagonist character of thecompounds of the invention. Finally, the ultrasonic vocalisation test inrats is effective in providing information on the anxiolytic effects ofthe products tested.

Accordingly, it will be possible to use the compounds of the presentinvention advantageously in diseases of the central nervous system,especially anxiety, depression, psychoses, schizophrenia, cognitivedisorders, stress and anorexia, and in the treatment of manifestationsof pain.

DETAIL DESCRIPTION OF THE INVENTION

More specifically, the present invention relates to the indanolcompounds of formula (I): ##STR5## wherein: R₁, R₂, R₃ and R₄, which maybe identical or different, each represent a hydrogen or halogen atom, a(C₁ -C₅)alkyl, (C₂ -C₅)alkenyl or (C₂ -C₅)alkynyl radical, thoseradicals being linear or branched chain, a cycloalkylalkyl radical inwhich the cycloalkyl moiety contains from 3 to 7 carbon atoms and thealkyl moiety contains from 1 to 5 carbon atoms, a trifluoromethyl, CHO,COOH, COO(C₁ -C₅)alkyl, CO(C₁ -C₅)alkyl, CH₂ OH, hydroxy, (C₁-C₅)-alkoxy, (C₂ -C₅)alkenoxy, (C₂ -C₅)alkynoxy, benzyloxy, cyano, nitroradical, ##STR6## wherein R₅ and R₆, which may be identical ordifferent, each represent a hydrogen atom or a (C₁ -C₅)alkyl, --CO(C₁-C₅)alkyl or --COO(C₁ -C₅)alkyl radical; or

R₁, R₂, R₃ and R₄, taken in pairs in adjacent positions, form with thecarbon atoms of the phenyl nucleus to which they are bonded a 5- to7-membered ring, containing one or more double bonds and composed ofatoms selected from carbon, oxygen, nitrogen and sulphur atoms, andothers radical, being not taken in pairs in adjacent positions, eachrepresent a hydrogen atom,

X-Y represents:

N--CH₂ , C═CH, CH--CH₂ or ##STR7## A forms with the two carbon atoms ofthe phenyl ring to which it is bonded a 5- to 7-membered heterocyclecontaining one or more double bonds and comprising one or two heteroatoms, which may be identical or different, selected from oxygen andsulphur atoms;

Z represents a hydrogen or halogen atom or a hydroxy or (C₁ -C₅)alkoxyradical, and

Z' represents a hydrogen atom or an oxo, hydroxy, (C₁ -C₅)alkoxy or CH₂OH radical,

in the form of the cis or trans isomers, it being possible for each ofthose to exist in racemic or optically active form, and addition saltsthereof with a pharmaceutically acceptable acid.

Accordingly, in formula (I), the ##STR8## group represents morespecifically: ##STR9## wherein Z and Z' are as defined hereinbefore.

The invention also extends to a process for the preparation of compoundsof formula I characterised in that a ketone of formula II: ##STR10##wherein R₁, R₂, R₃ and R₄ are as defined hereinbefore, is halogenated inthe α position of the ketone function to obtain a compound of formulaIII: ##STR11## wherein R₁, R₂, R₃ and R₄ are as defined hereinbefore andHal represents a chlorine, bromine or iodine atom,

which compound III is reacted with an amine of formula IV: ##STR12##wherein X-Y, A, Z and Z' are as defined hereinbefore, to yield acompound of formula V: ##STR13## wherein R₁, R₂, R₃, R₄, X-Y, A, Z andZ' are as defined hereinbefore,

which is reduced to a mixture of amino alcohols of formulae I trans andI cis: ##STR14## wherein R₁, R₂, R₃, R₄, X-Y, A, Z and Z' are as definedhereinbefore.

The compounds I trans and I cis are then separated by conventionalmethods for separating organic compounds, that is to say by fractionalrecrystallisation, separation over a silica column (flashchromatography) or separation by H.P.L.C. (High Performance LiquidChromatography).

The totality of the compounds I trans and I cis constitutes the totalityof the compounds of formula I.

Compounds of formula I wherein X-Y represents C═CH or CH--CH₂, that isto say compounds corresponding more specifically to formula Ia:##STR15## wherein: R₁, R₂, R₃, R₄, A, Z and Z' are as definedhereinbefore and

X'-Y' represents C═CH or CH--CH₂,

may also be prepared advantageously using the following methodcharacterised in that a compound of formula VI: ##STR16## wherein: A, Zand Z' are as defined hereinbefore, and

L represents a labile group selected from Br, I and OSO₂ CF₃,

is reacted with

diethyl(pyrid-1-yl)borane under the conditions of the Suzuki reaction,

to obtain a compound of formula VII: ##STR17## wherein A, Z and Z' areas defined hereinbefore, which is reacted with a compound of formula IIIdefined hereinbefore, to obtain a compound of formula VIII: ##STR18##wherein R₁, R₂, R₃, R₄, A, Z, Z' and Hal are as defined hereinbefore,

which is reduced with a metal borohydride in an alcoholic solvent toyield a mixture of amino alcohols of formulae I'a trans and I'a cis:##STR19## wherein R₁, R₂, R₃, R₄, A, Z and Z' are as definedhereinbefore,

which amino alcohols are, if desired, reduced again, with hydrogen inthe presence of a suitable catalyst, to compounds of formulae I"a transand I"a cis: ##STR20## wherein R₁, R₂, R₃, R₄, A, Z and Z' are asdefined hereinbefore,

and, when Z' represents an oxo radical, it is advantageous to start froma compound VII in which the oxo function is protected, for example inthe form of 1,3-dioxolane, and then deprotected at the level of thecompounds I'a trans and I'a cis or at the level of the compounds I"atrans and I"a cis,

the compounds I'a trans and I'a cis on the one hand and the compoundsI"a trans and I"a cis on the other hand are then separated byconventional methods for separating organic compounds, that is to say byfractional recrystallisation, separation over a silica column orseparation by H.P.L.C.

The totality of the compounds I'a trans, I'a cis, I"a trans and I"a cisconstitutes the totality of the compounds of formula Ia, which isincluded in formula I.

The halogenation of compound II is a standard reaction which can becarried out using a large number of reagents. When the halogen atom is abromine atom, the reaction can be carried out advantageously usingtetrabutylammonium tribromide in methanol and methylene chloride.

The reaction of compound III with compound IV is carried out, interalia, advantageously in dimethylformamide in the presence of K₂ CO₃.

The starting materials of formula II and of formula VI, when they arenot commercial products, were prepared starting from known substances,in accordance with processes described in the literature.

The optically active forms of the compounds of formula I were obtainedby separating the racemic forms of the compounds of formula I oranalogues thereof esterified at the alcohol function of the indanol, inaccordance with methods known in the literature.

The present invention relates also to pharmaceutical compositionscontaining as active ingredient at least one compound of formula I or aphysiologically tolerable salt thereof, mixed or in association with oneor more suitable pharmaceutical excipients.

The resulting pharmaceutical compositions are generally presented inunit dose form containing from 0.5 to 25 mg of active ingredient. Forexample, they may be in the form of tablets, dragees, gelatin capsules,suppositories, injectable or drinkable solutions, and may beadministered orally, rectally or parenterally.

The dosage may vary according to the age and weight of the patient, theroute of administration, the nature of the disease and associatedtreatments, and ranges from 0.5 to 25 mg of active ingredient, from 1 to3 times per day.

The following examples, which are given by way of non-limiting example,illustrate the present invention. The melting points were determinedeither using a Kofler hot plate (K) or a hot plate under a microscope(MK).

EXAMPLE 1 Cis-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-6-methoxyindan-1-ol

Step 1: 2-Bromo-6-methoxyindan-1-one

49.2 g (102 mmol) of tetra-n-butylammonium tribromide are added infractions over the course of 15 minutes, at room temperature, to 16.2 g(100 mmol) of 6-methoxy-indan-1-one dissolved in 400 ml of methanol and1 liter of dichloromethane, and the mixture is then stirred overnight atroom temperature. After evaporation, the residue is taken up in 500 mlof dichloromethane and washed twice with 250 ml of N hydrochloric acid.Drying over magnesium sulphate and concentration, and then rapidfiltration over 500 g of silica (eluant: dichloromethane) yield 23.4 gof the desired product.

Yield: 97%

Step 2: 2- 4-(2,3-Dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-6-methoxy-indan-1-one

A suspension prepared from 25.3 g (100 mmol) of the compound obtained inStep 1, 22.0 g (100 mmol) of (2,3-dihydro1,4!benzodioxin-5-yl)piperazine, 13.8 g (100 mmol) of potassiumcarbonate and 140 ml of dimethylformamide is stirred at room temperaturefor 20 hours. The mixture is then poured into 1.5 liters of water, andthe solid that forms (violet) is filtered off, rinsed with water anddried in vacuo to obtain 28.1 g of the expected product.

Yield: 74%

Step 3: Title compound

2.8 g (73.8 mmol) of sodium borohydride are added in fractions over thecourse of 15 minutes at room temperature to 28.0 g (73.6 mmol) of thecompound obtained in Step 2 in 220 ml of tetrahydrofuran. The mixture isstirred overnight at room temperature, and then for 4 hours at reflux.After evaporation, the residue is taken up in 1 liter ofdichloromethane, washed twice with 500 ml of water and then dried overmagnesium sulphate. After concentration, the residue is chromatographedover silica (eluant: dichloromethane/methanol 99/1, then 98/2). Theproduct eluted first corresponds to the cis isomer. Its stereochemistrywas demonstrated by IR, in solution in chloroform, according to themethod described by H. -J. Rimek et al. (Justus Liebigs Ann. Chem.,1969, 726, 25-29).

IR(CHCl₃): ν_(OH) bonded : 3380 cm⁻¹ (broad band)

m.p.(MK): 207-210° C.

EXAMPLE 2 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-6-methoxyindan-1-ol

The product eluted second in the chromatography carried out in Step 3 ofthe preceding sExample corresponds to the title compound. Itsstereochemistry was demonstrated according to the same method as above.

IR(CHCl₃): ν_(OH) free : 3580 cm⁻¹ (narrow band)

m.p.(MK): 145-148° C.

EXAMPLE 3 Cis-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-5-methoxyindan-1-ol

Prepared in the same manner as the compound of Example 1, but using5-methoxyindan-1-one instead of 6-methoxyindan-1-one in Step 1.

IR(CHCl₃): ν_(OH) bonded : 3400 cm⁻¹ (broad band)

m.p.(MK): 214-217° C.

EXAMPLE 4 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-5-methoxyindan-1-ol

Prepared in the same manner as the compound of Example 2, but using5-methoxyindan-1- one instead of 6-methoxyindan-1-one in Step 1 ofExample 1.

IR(CHCl₃): ν_(OH) free : 3700 cm⁻¹ and 3600 cm⁻¹ (narrow bands)

m.p.(MK): 137-140° C.

EXAMPLE 5 Cis-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!indan-1-ol

Prepared in the same manner as the compound of Example 1, but usingindan-1-one instead of 6-methoxyindan-1-one in Step 1.

IR(CHCl₃): ν_(OH) bonded : 3400 cm⁻¹ (broad band)

m.p.(MK): 196-198° C.

EXAMPLE 6 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!indan-1-ol

Prepared in the same manner as the compound of Example 2, but usingindan-1-one instead of 6-methoxyindan-1-one in Step 1 of Example 1.

IR(CHCl₃): ν_(OH) free : 3600 cm⁻¹ (narrow band)

m.p.(MK): 211-214° C.

EXAMPLE 7

(+)-Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!indan-1-ol

Step 1: (±)-Trans-1-(1-acetoxyindan-2-yl)-4-(2,3-dihydro1,4!benzodioxin-5-yl-piperazine

4.9 g of the compound obtained in Example 6 are treated at roomtemperature overnight with 706 ml of acetic anhydride and 141 ml ofpyridine. After concentration of the reaction mixture, the concentrateis take up in water and methylene chloride. After decanting, the organicphase is washed, dried, evaporated and purified by chromatography over asilica column to yield 5.2 g of expected product.

Step 2: Separation of the optical isomers

The 5.2 g of product obtained in the preceding Step are separated byH.P.L.C., over a chiral phase. An eluant prepared from anisooctane/ethanol/diethylamine mixture makes it possible to isolate 1.8g of a pure compound that corresponds to the first peak; the pure secondisomer (1.1 g) corresponding to the second peak is obtained using aneluant composed of an n-heptane/ethanol/diethylamine mixture.

Step 3: Title compound

The 1.8 g of the first product obtained in the chromatographicseparation of Step 2 are treated with 1.28 g of potassium hydroxide, 18ml of water and 160 ml of methanol, at reflux for 2 hours. Concentrationis carried out and the concentrate is taken up in methylene chloride,washed with water, dried and evaporated to yield, afterrecrystallisation of the residue, 0.44 g of a product that melts at184-186° C. (MK) and corresponds to the expected structure in anenantiomeric excess of 99%.

α!²⁰° C. (c=0.5% in CH₃ OH):

    ______________________________________    λ nm           589        578    546      436  365    ______________________________________    α°           +22.1      +22.9  +26.1    +47.2                                           +79.6    ______________________________________

EXAMPLE 8 (-)-Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!indan-1-ol

The 1.1 g of the second product obtained in the chromatographicseparation are treated in the same manner as in the course of Step 3 ofExample 7 to yield 0.27 g of a product that melts at 186-189° C. (MK)and corresponds to the expected structure in an enantiomeric excess ofmore than 97%.

α!²⁰° C. (c=0.5% in CH₃ OH):

    ______________________________________    λ nm           589        578    546      436  365    ______________________________________    α°           -20.9      -22.1  -25.4    -45.7                                           -77.1    ______________________________________

EXAMPLE 9 Cis-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-6-hydroxyindan-1-ol

0.77 g of the compound of Example 1 is suspended at -20° C. in methylenechloride. 4.1 ml of a boron tribromide solution (1M in methylenechloride) are added dropwise thereto. The mixture is stirred for 3 hoursat -20° C. and is then allowed to return to room temperature and issubsequently left for 3 days with stirring. The resulting precipitate isfiltered off and washed with methylene chloride. It is solidified fromwater to yield 0.58 g of a product which corresponds to the hydrobromideof the expected product. Freeing of the salt by a sodium hydrogencarbonate solution, extraction with methylene chloride, evaporation andsolidification yield 0.25 g of the expected product.

The compounds of the following Examples were prepared from thecorresponding starting materials by proceeding as in Example 1:

EXAMPLE 10

Cis-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-5-fluoroindan-1-ol

m.p. (MK)=210-213° C.

EXAMPLE 11 Cis-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!-5-fluoroindan-1-ol

m.p. (MK)=197-201° C.

EXAMPLE 12 Cis-2-4-(3,4-dihydro-2H-chromen-8-yl)piperazin-1-yl!-5-fluoroindan-1-ol

m.p.(MK)=209-210° C.

EXAMPLES 13 TO 16

The compounds of the following Examples were prepared from thecorresponding starting materials in the same manner as the compound ofExample 2:

EXAMPLE 13 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-5-fluoroindan-1-ol

m.p. (MK)=220-224° C.

EXAMPLE 14 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!-5-fluoroindan-1-ol

m.p. (MK)=204-209° C.

EXAMPLE 15 Trans-2-4-(3,4-dihydro-2H-chromen-8-yl)piperazin-1-yl!-5-fluoroindan-1-ol

m.p. (MK)=148-150° C.

EXAMPLE 16

Trans-2-{4- 2,3-dihydro-2-(hydroxymethyl)1,4!-benzodioxin-5-yl!piperazin-1-yl}-6-methoxyindan-1-ol

EXAMPLE 17 Trans-2-{4- 7-chloro-2,3-dihydro-2-(hydroxymethyl)1,4!-benzodioxin-5-yl!piperazin-1-yl}-5-fluoroindan-1-ol EXAMPLE 18Cis-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)-1,2,3,6-tetrahydropyrid-1-yl!indan-1-ol

Step 1: 4-(2,3-Dihydro 1,4!benzodioxin-5-yl)pyridine

14.7 mmol of diethyl(pyrid-4-yl)borane, 22 mmol of 5-bromo-2,3-dihydro1,4!-benzodioxine, 44.1 mol of KOH in powder form, 7.4 mmol oftetrabutylammonium bromide and 0.74 mmol oftetrakis(triphenylphosphine)palladium in 75 ml of tetrahydrofuran aremixed at room temperature, and the mixture is then refluxed for 24hours. 225 ml of ethyl acetate are added and the mixture is washed witha saturated sodium chloride solution. Drying is carried out over MgSO₄,followed by evaporation and purification over a silica column (eluantCH₂ Cl₂, then CH₂ Cl₂ /CH₃ COOC₂ H₅ 80/20).

Yield: 52%

Step 2: 4-(2,3-Dihydro1,4!benzodioxin-5-yl)-1-(indan-1-one-2-yl)-pyridinium bromide

2.41 g of the compound obtained in the preceding Step and 2.45 g of2-bromo-indan-1-one are dissolved in 35 ml of acetone and refluxed for24 hours. After cooling, the solid is filtered off, rinsed with acetoneand dried in vacuo to yield 2.7 g of product which corresponds to theexpected structure.

Step 3: Title compound

1.18 g of sodium borohydride are added in fractions over the course of30 minutes at room temperature to 2.6 g of the compound obtained in thepreceding Step suspended in 50 ml of methanol (very strongly exothermic)and the mixture is then stirred at room temperature for 30 minutes. 2.8ml of acetic acid are then added and evaporation to dryness is carriedout. The residue is taken up in 50 ml of N sodium hydroxide solution andextracted twice with 50 ml of methylene chloride. The organic phases arewashed with water, dried, evaporated and chromatographed over silica,eluant CH₂ Cl₂ /CH₃ COOC₂ H₅ 90/10, then CH₂ Cl₂ /CH₃ OH 99/1. The firstproduct eluted is recrystallised from ethanol to yield 0.27 g ofexpected product.

m.p. (MK)=109-112° C.

The cis stereochemistry of the product is demonstrated by infrared, insolution in chloroform, according to the method described by H. J. Rimeket al. (Justus Liebigs Ann. Chem., 1969, 726, 25-20).

IR(CHCl₃): ν_(OH) bonded : 3400 cm⁻¹ (broad band)

EXAMPLE 19 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)-1,2,3,6-tetrahydropyrid-1-yl!indan-1-ol

The product eluted second in the chromatography carried out in Step 3 ofthe preceding Example corresponds to the title compound.

m.p. (MK)=182-184° C.

Its stereochemistry was demonstrated according to the method used in thepreceding Example.

IR(CHCl₃): ν_(OH) free : 3600 cm⁻¹ (narrow band)

EXAMPLE 20 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)-1,2,3,6-tetrahydropyrid-1-yl-5-fluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 18 and19, but using 2-bromo-5-fluoroindan-1-one instead of 2-bromoindan-1-onein Step 2 of Example 18.

The melting point (MK) of the title compound is 198-202° C.

EXAMPLE 21 Trans-2-4-(3,4-dihydro-2H-thiochromen-8-yl)-1,2,3,6-tetrahydropyrid-1-yl!-5-fluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 18 and19, but using 3,4-dihydro-2H-thiochromen-8-yl triflate instead of5-bromo-2,3-dihydro 1,4!-benzodioxine in Step 1 of Example 18, and using2-bromo-5-fluoro-indan-1-one instead of 2-bromo-indan-1-one in Step 2 ofExample 18.

The melting point (MK) of the title compound is 143-147° C.

EXAMPLE 22 Trans-2-4-(3,4-dihydro-2H-chromen-8-yl)-1,2,3,6-tetrahydropyrid-1-yl!-5-fluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 18 and19, but using 8-bromo-3,4-dihydro-2H-chromene in Step 1 of Example 18,and using 2-bromo-5-fluoro-indan-1-one in Step 2 of Example 18.

EXAMPLE 23 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!indan-1-ol

0.44 g of the compound obtained in Example 19 dissolved in 20 ml of CH₃OH is hydrogenated at room temperature and atmospheric pressure in thepresence of platinum oxide. Purification over a silica column andrecrystallisation from acetonitrile yield 0.17 g of a product, thestructure of which corresponds to that of the expected product.

m.p. (MK)=173-174° C.

EXAMPLE 24 Trans-2- 4-(benzofuran-7-yl)piperid-1-yl!-5-fluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 18, 19and 23, but using 7-bromobenzofuran instead of 5-bromo-2,3-dihydro1,4!benzodioxine in Step 1 of Example 18, and using2-bromo-5-fluoroindan-1-one instead of 2-bromo-indan-1-one in Step 2 ofExample 18.

The melting point (MK) of the title compound is 170-172° C.

EXAMPLE 25 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!-6-fluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 18, 19and 23, but using 2-bromo-6-fluoro-indan-1-one instead of2-bromo-indan-1-one in Step 2 of Example 18.

The melting point (MK) of the title compound is 159-163° C.

EXAMPLE 26 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!-5-methylindan-1-ol

Prepared using, in succession, the methods described in Examples 18, 19and 23, but using 2-bromo-5-methyl-indan-1-one in Step 2 of Example 18.

The melting point (MK)of the title compound is 191-192° C.

EXAMPLE 27 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!6-methylindan-1-o

Prepared using, in succession, the methods described in Examples 18, 19and 23, but using 2-bromo-6-methylindan-1-one in Step 2 of Example 18.

The melting point (MK) of the title compound is 225-226° C.

EXAMPLE 28 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!-5,6-difluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 18, 19and 23, but using 2-bromo-5,6-difluoroindan-1-one in Step 2 of Example18.

The melting point (MK) of the title compound is 167-169° C.

EXAMPLE 29 Trans-2-4-(3,4-dihydro-6-fluoro-2H-chromen-8-yl)piperid-1-yl!-5-fluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 18, 19and 23, but using 3,4-dihydro-2H-6-fluorochromen-8-yl triflate insteadof 5-bromo-2,3-dihydro 1,4!-benzodioxine in Step 1 of Example 18, andusing 2-bromo-5-fluoroindan-1-one instead of 2-bromoindan-1-one in Step2 of Example 18.

The melting point (MK) of the title compound is 160-162° C.

EXAMPLE 30 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!-5,6-methylenedioxyindan-1-ol

Prepared using, in succession, the methods described in Examples 18, 19and 23, but using 2-bromo-5,6-methylenedioxyindan-1-one in Step 2 ofExample 18.

The melting point (MK) of the title compound is 212-215° C.

EXAMPLE 31 Trans-2-4-(2,3-dihydrobenzofuran-7-yl)piperid-1-yl!-5-fluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 18, 19and 23, but using 7-bromo-2,3-dihydrobenzofuran in Step 1 of Example 18,and using 2-bromo-5-fluoro-indan-1-one in Step 2 of Example 18.

The melting point (MK) of the title compound is 215-217° C.

EXAMPLE 32 Trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)-4-hydroxypiperid-1-yl!-5-fluoroindan-1-ol

Prepared using, in succession, the methods described in Examples 1 and2, but using 5-fluoroindan-1-one in Step 1 of Example 1, and using4-(2,3-dihydro 1,4!benzodioxin-5-yl)-4-hydroxypiperidine in Step 2 ofExample 1.

EXAMPLES 33 to 42

The compounds of the following Examples were prepared from thecorresponding starting materials by proceeding as described in Examples24 to 31:

EXAMPLE 33 Trans-2- 4-(7-chloro-2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!-5-fluoroindan-1-ol

m.p. (MK)=175-177° C.

EXAMPLE 34 Trans-2-4-(3,4-dihydro-2H-chromen-8-yl)piperid-1-yl!-5-fluoroindan-1-ol EXAMPLE35 Trans-6-bromo-2-4-(3,4-dihydrobenzodioxin-5-yl)piperid-1-yl!indan-1-ol EXAMPLE 36Trans-6-cyano-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!indan-1-ol EXAMPLE 37Trans-6-carbamoyl-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!indan-1-ol EXAMPLE 38 Trans-2-4-(2,3-dihydro1,4!benzodioxin-5-yl)piperid-1-yl!-6-trifluoromethylindan-1-ol EXAMPLE39 Trans-2- 4-(3,4-dihydro 1,4!-2H-chromen-8-yl)piperid-1-yl!indan-1-olEXAMPLE 40 Trans-2-{4- 2,3-dihydro-2-(hydroxymethyl)1,4!benzodioxin-5-yl!piperid-1-yl}-5-fluoroindan-1-ol EXAMPLE 41Trans-2-{4-(3,4-dihydro)-4-oxo-2H-chromen-8-yl!piperid-1-yl}-5-fluoroindan-1-ol,

In this case additionally using the method of protecting/deprotectingthe oxo function.

EXAMPLE 42 Trans-2-{4-(3,4-dihydro)-4-hydroxy-2H-chromen-8-yl!piperid-1-yl}-5-fluoroindan-1-olEXAMPLE 43 Pharmacological Study

A. In vitro study

Determination of affinity for human h5-HT_(1A) receptors

Affinity was determined by competition experiments with ³ H!-8-OH-DPAT(NEN, Les Ulis, France). The membranes prepared from CHO cellstransfected with the human 5-HT_(1A) receptor were prepared as describedby Newman-Tancredi et al., (Neuropharmacol, 1997, 36, 451-459). Themembranes are incubated in triplicate with 0.4 nM ³ H!-8-OH-DPAT and thecold ligand in a final volume of 1.0 ml for two and a half hours at 25°C. The incubation buffer contains 25 mM HEPES-NaOH(pH 7.4) and 5 mMMgCl₂. The non-specific binding is determined using 10 μM 5-HT. At theend of incubation, the incubation medium is filtered through WHATMANGF/B filters that have been impregnated with 0.1% polyethylenimine andhave been washed three times with 5 ml of cooled buffer. Theradioactivity retained on the filters is determined by liquidscintillation counting. The binding isotherms are analysed by non-linearregression using `PRISM` software (Graphpad Software Inc., S. Diego,USA) to determine the IC₅₀ values. These are converted into dissociationconstants (K_(i)) by means of the Cheng-Prusoff equation:

    K.sub.i =IC.sub.50 /(1+L/K.sub.d)

wherein L is the concentration of ³ H!-8-OH-DPAT and K_(d) is thedissociation constant of ³ H!-8-OH-DPAT for the human h5-HT_(1A)receptor (0.65 nM).

By way of Example and to illustrate the activity of the compounds of theinvention, the compound of Example 6 has a K_(i) of 1.73 nM.

Determination of affinity for α₁ receptors of rats

Affinity was determined by competition experiments with ³ H!-prazosin(NEN, Les Ulis, France). The membranes are prepared from frontal cortexof rat as described by Millan et al. (J. Pharmacol. Exp. Ther, 1995,275, 885-898). The membranes are incubated in triplicate with 0.2 nM ³H!-8-OH-DPAT and the cold ligand in a final volume of 1.0 ml for 60minutes at 25° C. The incubation buffer contains 50 nM TRIS-HCl (pH7.4), 4 mM CaCl₂, 0.1% (w/v) of ascorbic acid and 10 μM pargyline. Thenon-specific binding is determined using 10 μM phentolamine. At the endof incubation, the incubation medium is filtered through WHATMAN GF/Bfilters that have been impregnated with 0.1% polyethylenimine and havebeen washed three times with 5 ml of cooled buffer. The radioactivityretained on the filters is determined by liquid scintillation counting.The binding isotherms are analysed by non-linear regression using`PRISM` software (GraphPad Software Inc., S. Diego, USA) to determineIC₅₀ values. These are converted into dissociation constants (K_(i)) bymeans of the Cheng-Prusoff equation:

    K.sub.i =IC.sub.50 /(1+L/K.sub.d)

wherein L is the concentration of ³ H!-prazosin and K_(d) is thedissociation constant of ³ H!-prazosin for the α₁ receptor (0.1 nM).

By way of Example and to illustrate the activity of the compounds of theinvention, the compound of Example 6 has a K_(i) of 932 nM.

These two results illustrate well the excellent selectivity of thecompounds of the invention for the 5-HT_(1A) receptor compared with thatfor the α₁ receptor, which should result in products having nocardiovascular side-effects and that are accordingly safer to use.

B. In vivo study

1. "In vivo" recording of unitary extracellular electrical activity inthe dorsal nucleus of the raphe in rats (pre-synaptic ⁵ -HT_(1A)receptors)

Principle

The administration of a 5-HT_(1A) serotoninergic agonist decreases thedischarge frequency of neurons in a dose-dependant manner. That effectis reversed by the selective 5-HT_(1A) antagonist, WAY 100,635.

Method

The rats are anaesthetised with chloral hydrate (400 mg/kg, i.p.) andplaced in a stereotaxis apparatus (Unimecanique, France) aftercatheterisation of the femoral vein. The level of anaesthesia ismaintained by i.p. administration of chloral hydrate every hour; therectal temperature is maintained at 37±1° C. by means of athermostatically controlled heated cover. A tungsten microelectrode (10MΩ, 1 μM) is inserted using an electronic microinsertion device(Unimecanique, France) into the dorsal nucleus of the raphe (AP: -7.8bregma; L : 0.0; H: 5.0-6.5 dura; Paxinos and Watson Atlas, 1986). Thepotentials of the serotoninergic cells are characterised by theirmorphology (positive/negative biphase potentials, of a duration of lessthan 2.5 msec) and their slow and regular discharge rhythm of from 0.5to 2.5 Hz. A single cell per animal is recorded.

After a period of ≧5 min (basal activity) and a first injection ofcarrier (distilled water to which a few drops of dilute lactic acid havebeen added, pH adjusted to 5 with 1N NaOH), the compound of theinvention is administered intravenously in cumulatively increasing dosesat intervals of 5 minutes.

Analysis of the results

Acquisition of the data is effected by the software Spike2 (CambridgeElectronic Design, England). The discharge frequency is measured overone minute at the maximum variation between each injection and isexpressed as a percentage variation in relation to the basal activity(average of the 5 minutes preceding the first treatment) defined as100%. The ID₅₀ is calculated using a simple linear regression methodwith repeated measurements.

Results

By way of Example, the following Table shows the effects of the compoundof Example 6.

    ______________________________________    Doses                                WAY 100, 365    μg/kg i. v.           0       0.25    0.5   1       31 μg/kg    ______________________________________    Example 6           98.11 ±                   73.84 ±                           52.23 ±                                 36.16 ± 2.52                                         140.48 ± 20.11            2.21   14.14   19.38    ______________________________________     Individual values (n = 3). Mean ± standard error of the mean.

The ID₅₀ of the compound of Example 6 in this test is 0.59 μg/kg whenthe product is administered intravenously. The result shows that thesite of action, in vivo, of the compounds of the invention is indeedlocated at the level of the 5-HT_(1A) receptors, as has already beenshown in vitro, and that the compound of Example 6 behaves like a5-HT_(1A) serotoninergic agonist at the pre-synaptic level.

2. Body temperature test in rats (post-synaptic 5-HT_(1A) receptors)

Principle

The administration of a 5-HT_(1A) serotoninergic agonist, such as, forexample, 8-OH-DPAT, brings about a decrease in body temperature in adose-dependent manner. That effect is reversed by 5-HT_(1A) antagonists,as has been shown by M. J. Millan (J. Pharmacol. Exp. Ther., 1993, 264,1346-1376). According to the protocol described by that author,compounds of the invention which when administered on their own bringabout a decrease in body temperature will be identified as post-synaptic5-HT_(1A) serotoninergic agonists. On the other hand, compounds of theinvention that reverse the hypothermia induced by the prototypical5-HT_(1A) agonist 8-OH-DPAT will be identified as post-synaptic5-HT_(1A) antagonists.

Results

By way of Example and to illustrate the effects of the compounds of theinvention, the compound of Example 6 reverses the effects of 8-OH-DPATat an ID₅₀ of 1.3 mg/kg s.c. It thus behaves like a post-synaptic5-HT_(1A) serotoninergic antagonist.

3. Ultrasonic vocalisation test in rats

Principle

When a rat is placed in an environment previously associated with anunpleasant experience (electric shocks to the paws), its anxiety isshown by the emission of inaudible cries (or ultrasonic vocalisations).The anxiolytic activity of a compound is demonstrated by a reduction inthe duration of those vocalisations.

Apparatus

Standard cages (Coulbourn Instruments), placed in sound-absorbingventilated boxes, are fitted with a floor composed of electrifiablemetal bars (shock generator and scrambler Med Associates Inc) and with amicrophone located in the centre of the ceiling. The ultrasonic noisesare converted into an audible range (bat-detector Buitenbedrijf). Thesignals modified in that manner are filtered and then processed (RTSsoftware, Engineering Design). The spectrograms obtained are recorded onDAT tapes.

Method

Male Wistar rats weighing 180-200 g on their arrival are placed in cagesof four with free access to water and food from five days before thestart of the study until the end of the study. The procedure employed isdivided into three successive stages separated by 24 hours, calledtraining, selection and test. During the training period, the animalsare placed individually into cages where they receive six electricshocks (0.8 mA, 8 s) distributed randomly over a period of sevenminutes. Selection comprises placing each animal in a cage for twominutes where it receives a single shock and putting it back in the cagethirty minutes later to record the ultrasonic vocalisations for a periodof ten minutes; those animals in which the duration of the vocalisationsis less than 90 seconds are excluded from the remainder of theexperiment. The test phase proceeds in a similar manner to the selectionstage, except that the compounds or the carrier are administered at theend of the two-minute period.

Results

By way of Example, the following Table shows the effects of the compoundof Example 6 administered subcutaneously in a volume of 1 ml/kg.

    ______________________________________                duration of the                ultrasonic vocalisations (s)    dose        mean ± s. e. m. (n)    mg/kg s. c. Example 6    ______________________________________    0                     230 ± 17                                   (8)    0.04                  170 ± 62                                   (6)    0.16                   28 ± 14                                   (3) **    2.5                    8 ± 8                                   (5) **    ______________________________________     s. e. m.: standard error of the mean     n: number of rats     comparison with carrier (Dunnett test): ** p < 0.01

At doses of 0.16 and 2.5 mg/kg, that compound brings about a reductionin the duration of the vocalisations, indicating its anxiolyticactivity.

We claim:
 1. An indanol compound selected from those of formula I:##STR21## wherein: R₁, R₂, R₃ and R₄, which may be identical ordifferent, each represents hydrogen or halogen, (C₁ -C₅)alkyl, (C₂-C₅)alkenyl, or (C₂ -C₅)alkynyl, those radicals being linear orbranched, cycloalkylalkyl in which cycloalkyl contains 3 to 7 carbonatoms inclusive and alkyl contains 1 to 5 carbon atoms, inclusivetrifluoromethyl, CHO, COOH, COO(C₁ -C₅)alkyl, CO(C₁ -C₅)alkyl, CH₂ OH,hydroxy, (C₁ -C₅)-alkoxy, (C₂ -C₅)alkenoxy, (C₂ -C₅)alkynoxy, benzyloxy,cyano, nitro, or a group of formula: ##STR22## wherein R₅ and R₆, whichmay be identical or different, each represents hydrogen, halogen, (C₁-C₅)alkyl, --CO(C₁ -C₅)alkyl, or --COO(C₁ -C₅)alkyl,X-Y representsrespectively:N--CH₂ , A forms with the two carbon atoms of the phenylring to which it is bonded a 5- to 7-membered heterocycle containing oneor more double bonds and comprising one or two heteroatoms, which may beidentical or different, selected from oxygen and sulphur, Z representshydrogen or halogen, hydroxy, or (C₁ -C₅)alkoxy, Z' represents hydrogen,oxo, hydroxy, (C₁ -C₅)alkoxy, or CH₂ OH,in the form of cis or transisomers, each of those being in racemic or optically active form, andpharmaceutically-acceptable acid addition salts thereof.
 2. A compoundof claim 1 wherein:R₁, R₂, R₃, R₄ and X-Y are as defined in claim 1 andthe ##STR23## group represents more specifically: ##STR24## wherein Zand Z' are as defined in claim 1, in the form of cis or trans isomers,each of those being in racemic or optically active form, andpharmaceutically-acceptable acid addition salts thereof.
 3. A compoundof claim 1 which is trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-6-methoxyindan-1-ol.
 4. A compoundof claim 1 which is trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-5-methoxyindan-1-ol.
 5. A compoundof claim 1 which is trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!indan-1-ol.
 6. A compound of claim 1which is (+)-trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!indan-1-ol
 7. A compound of claim 1which is (-)-trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!indan-1-ol.
 8. A compound of claim 1which is trans-2- 4-(2,3-dihydro1,4!benzodioxin-5-yl)piperazin-1-yl!-5-fluoroindan-1-ol.
 9. A compoundof claim 1 which is trans-2-4-(3,4-dihydro-2H-chromen-8-yl)piperazin-1-yl!-5-fluoroindan-1-ol.
 10. Acompound of claim 1 which is trans-2-{4- 2,3-dihydro-2-(hydroxymethyl)1,4!-benzodioxin-5-yl!piperazin-1-yl}-6-methoxyindan-1-ol.
 11. A methodfor treating a living body afflicted with a condition selected fromanxiety, depression, psychoses, schizophrenia, and pain, comprising thestep of administering to the living body an amount of a compound ofclaim 1 which is effective for alleviation of said condition.
 12. Apharmaceutical composition comprising as active principle an effectiveamount of a compound as claimed in claim 1, together with one or morepharmaceutically-acceptable excipients or vehicles.
 13. A method fortreating a living body afflicted with a condition selected from anxiety,depression, psychoses, schizophrenia, and pain, comprising the step ofadministering to the living body an amount of a compound of claim 2,which is effective for alleviation of said condition.
 14. Apharmaceutical composition comprising as active principle an effectiveamount of a compound as claimed in claim 2, together with one or morepharmaceutically-acceptable excipients or vehicles.